Dopamine (DA) is a critical neuromodulator in neural circuits for motor control, cognition and reward. A chief target of DA modulation is signaling of the excitatory neurotransmitter, glutamate. What are the basic principles for DA modulation of glutamatergic signaling and plasticity? Data addressing this question are maddeningly complex. Much of this complexity may be due to variations between cell types and circuits in which DA has been studied. What other factors might contribute to the heterogeneity? Using an ex vivo brain slice preparation of the nucleus accumbens (NAc)-a central component of the neural reward circuit-our pilot studies provide evidence for two additional factors: 1) in vivo exposure t novel stimuli and 2) the timing of DA signaling in relation to long-term potentiation (LTP) induction. We find that a brief exposure to novelty enables DA to induce a long-lasting depression in NAc AMPAR synaptic strength. We also find that prior DA signaling boosts the ability of tetanic stimulation to induce robust LTP. Using direct and sensitive electrophysiologica measures, we will investigate the roles for novelty and timing in DA modulation of NAc AMPARs. We expect our studies to inform new guiding principles for dopamine modulation in health and disease.